The p53 tumor suppressor protein can prevent the formation of tumors through several mechanisms, including the activation of cell-cycle checkpoints to prevent damaged cells from proliferation (cell-cycle arrest and DNA repair), the promotion of senescence (permanent cell-cycle arrest), and/or the triggering of cell death (apoptosis or autophagy). It can also impede cell migration, metabolism, or angiogenesis, which are needed for cancer cell progression and metastasis. Mutations of the tumor suppressor gene TP53 are detected in ˜50% of all types of human cancers, while the functions and stability of the p53 protein are often abrogated via posttranslational mechanisms in the rest of human cancers that contain wild type TP53. Therefore, the restoration or reactivation of wild-type p53 function can lead to rapid elimination of tumors. As such, compounds that target the p53 pathway have become promising anticancer drug candidates, and several of them have entered clinical trials. For instance, Nutlin-3 and MI-219 can increase p53 level and activity by interfering with the p53-MDM2 binding. Even though there have been extensive endeavors to find small molecules that target the p53 pathway, none has yet proven to be clinically effective therapeutics due to the inherent undesirable toxicity to normal cells and tissues.
Recent efforts in silico screening and cellular-based assays have shown that Inauhzin (INZ) and some of its analogs (FIG. 7) comprise a class of small molecules that effectively activate p53 and promote p53-dependent apoptosis of human cancer cells, apparently without causing genotoxic stress. In addition, INZ appears to stabilize p53 by increasing p53 acetylation and preventing MDM2-mediated ubiquitylation of p53 in cells. Remarkably, INZ inhibited cell proliferation, induced senescence and tumor-specific apoptosis, and repressed the growth of xenograft tumors derived from p53-harboring lung cancer H460 and colon cancer HCT116+/+ cells without causing measurable toxicity to normal tissues.
INZ is an effective anti-cancer agent which can be used either alone or in combination with Nutlin treatment or DNA damage agents such as Cisplatin and Doxorubicin. A single treatment with Nutlin-3 is less efficient in inhibiting the growth or in promoting apoptosis of some cancer cells, such as HCT116+/+, H460, or A549, in xenograft tumor models even though these cells contain wild type p53. The combination of INZ with Nutlin-3 synergistically promotes apoptosis in HCT116+/+ and H460 cell lines in a p53-dependent fashion. This combination also synergistically activates p53 in xenograft tumors derived from these cancer cells and significantly suppresses their growth.
To further characterize the structural features essential for the activity of this group of small molecules to induce p53 and to suppress cell proliferation, a structure-activity relationship (SAR) analyses of INZ analogs was performed. A number of new INZ analogs were synthesized and evaluated for their ability to induce p53 and inhibit cell growth using cell-based assays. This study not only revealed critical chemical groups for INZ activity, but also lead to the discovery of INZ derivative 37, a compound that displays better potency in p53 induction and cancer cell growth inhibition than does INZ.
Additional information regarding small molecule modulators of SIRT1 activity activating p53 and suppressing tumor growth can be found in International Patent Application Publication Number WO 2012/135149, published Aug. 20, 2009 base on PCT/US/2012/030619 having an International Filing Date of Mar. 26, 2012, which claims the benefit of U.S. provisional patent Applications Nos. 61/467,511 filed on Mar. 25, 2011, 61/579,519 filed on Dec. 22, 2011, and 61/583,040 filed on Apr. 1, 2012, each of which are hereby incorporated by reference in their entirety.
According to one embodiment of the present disclosure, a composition is provided, the composition comprising a compound according to Formula (I) or a pharmaceutically acceptable salt thereof:
wherein, G2 is:

X is: CH2, O, NH, or S;
R1 is: CH3, CH3CH2, CH3CH2CH2, or CH3CH2CH2CH2;
Y is: H,
or R2;
R2 is:

R3 is H, an alkyl group, or a halogen;
R4 is H, a halogen, or OCH3; and
R5 is:

In one particular embodiment, the compound according to Formula I is:
or a pharmaceutically acceptable salt thereof. In another particular embodiment, the composition comprises a compound according to Formula (I), wherein G2 is
X is CH2, R1 is CH3CH2, Y is H, R3 is H, and R4 is H. In still another particular embodiment, the composition comprises a compound according to Formula (I), wherein G2 is
X is CH2, Y is R2, R1 is CH3CH2, R2 is
R3 is H, and R4 is H.
In another embodiment, of the present disclosure, a composition is provided, the composition comprising a compound according to Formula (I) or a pharmaceutically acceptable salt thereof,
wherein, G2 is:

X is: CH2, O, or S;
R1 is: CH3CH2;
Y is: H;
R3 is H; and R4 is H, Cl, or OCH3.
In another embodiment of the present disclosure, a composition is provided, the composition comprising a compound according to Formula (I) or a pharmaceutically acceptable salt thereof:
wherein, G2 is:

X is: S;
R1 is: CH3CH2, or CH3CH2CH2CH2;
Y is: H;
R3 is H, OCH3, an alkyl group, or a halogen;
R4 is H.
In another embodiment of the present disclosure, a composition is provided, the composition comprising a compound according to Formula (I) or a pharmaceutically acceptable salt thereof:
wherein G2 is:

X is: S;
R1 is: CH3CH2;
Y is:

R3 is H;
R4 is H; and
R5 is:

In another embodiment of the present disclosure, a composition is provided, the composition comprising a compound according to Formula (I) or a pharmaceutically acceptable salt thereof:
wherein, G2 is:

X is: S;
R1 is: CH3CH2;
Y is: R2;
R2 is:

R3 is H; and
R4 is H.
According to another embodiment of the present disclosure, a composition is provided, the composition comprising a compound according to Formula (I) or a pharmaceutically acceptable salt thereof:
wherein, G2 is:

X is: CH2, O, NH, or S;
R1 is: CH3, CH3CH2, CH3CH2CH2, or CH3CH2CH2CH2;
Y is: H,
CH2CH2OH, CH2CH2CCH;
or R2;
R2 is:

R3 is H, an alkyl group, OCH3 or a halogen;
R4 is H, a halogen, or OCH3; and
R5 is:

In another embodiment of the present disclosure, a composition is provided, the composition comprising a compound according to Formula (I) or a pharmaceutically acceptable salt thereof: wherein, G2 is:

X is: CH2;
R1 is: CH3CH2;
Y is: H, CH2CH2OH, CH2CH2CCH; or R2;
R2 is:

R3 is H, an alkyl group, OCH3, or a halogen; and
R4 is H.
In another embodiment, a method of increasing apoptosis is provided, the method, comprising the steps of contacting at least one eukaryotic cell with an effective amount of any of the above compositions containing a compound according to Formula (I) or a pharmaceutically acceptable salt thereof.
In another embodiment, a method of treating a patient is provided, the method comprising the steps of administering at least one therapeutically effective dose of any of the above compositions containing compound according to Formula (I) or a pharmaceutically acceptable salt thereof to a human or to an animal. In a particular embodiment, the compound of Formula I is co-administered to said human or said animal along with a therapeutically effective dose of at least one chemotherapeutic agent. In another particular embodiment, the human is diagnosed with cancer. In another particular embodiment, the human is diagnosed with lung cancer. In another particular embodiment, the chemotherapeutic agent is selected from the group consisting of: cisplatin and doxorubicin.